1. Field of the Invention
This invention is in the field of implantable biological prostheses. The present invention is a non-antigenic, resilient, completely bioremodelable, biocompatible tissue prosthesis which can be engineered into a variety of shapes and used to repair, augment, or replace mammalian tissues and organs. Each layer of the prosthesis is gradually degraded and remodeled by the host's cells which replace the implanted prosthesis in its entirety to restore structure and function and is useful for organ repair and reconstruction. Thus, the prosthesis acts as a template by which the host's cells will remodel themselves through a process that will replace the prosthesis collagen molecules with the appropriate host cells in order to restore and replace the original host tissue or organ.
2. Brief Description of the Background of the Invention
Despite the growing sophistication of medical technology, repairing and replacing damaged tissues remains a frequent, costly, and serious problem in health care. Currently implantable prostheses are made from a number of synthetic and treated natural materials. The ideal prosthetic material should be chemically inert, non-carcinogenic, capable of resisting mechanical stress, capable of being fabricated in the form required, and sterilizable, yet not be physically modified by tissue fluids, excite an inflammatory or foreign body reaction, induce a state of allergy or hypersensitivity, or, in some cases, promote visceral adhesions (Jenkins S. D., et al. Surgery 94(2):392-398, 1983),
For example, body wall defects that cannot be closed with autogenous tissue due to trauma, necrosis or other causes require repair, augmentation, or replacement with synthetic mesh. In reinforcing or repairing abdominal wall defects, several prosthetic materials have been used, including tantalum gauze, stainless mesh, DACRON®, ORLON®, FORTISAN®, nylon, knitted polypropylene (MARLEX®), microporous expanded-polytetrafluoroethylene (GORE-TEX®), dacron reinforced silicone rubber (SILASTlC®), polyglactin 910 (VICRYL®), polyester (MERSILENE®), polyglycolic acid (DEXON®) processed sheep dermal collagen (PSDC®) crosslinked bovine pericardium (PERI-GUARD®), and preserved human dura (LYODURA®). No single prosthetic material has gained universal acceptance.
The major advantaged of metallic meshes are that they are inert, resistant to infection and can stimulate fibroplasia. Their major disadvantage is the fragmentation that occurs after the first year of implantation as well as the lack of malleability. Synthetic meshes have the advantage of being easily molded and, except for nylon, retain their tensile strength in the body. European Patent No. 91122196.8 to Krajicek details a triple-layer vascular prosthesis which utilizes non-resorbable, synthetic mesh as the center layer. The synthetic textile mesh layer is used as a central frame to which layers of collagenous fibers can be added, resulting in the tri-layered prosthetic device. The major disadvantage of a non-resorbable snythetic mesh is lack of inertness, susceptibility to infection, and interference with wound healing.
In contrast to the non-resorbable mesh disclosed in Krajicek (E.P. No. 91122196.8), absorbable synthetic meshes have the advantage of impermanence at the site of implantation, but often have the disadvantage of losing their mechanical strength, because of dissolution by the host, prior to adequate cell and tissue ingrowth.
The most widely used material for abdominal wall replacement and for reinforcement during hernia repairs is MARLEX®; however, several investigators reported that with scar contracture, polypropylene mesh grafts became distorted and separated from surrounding normal tissue in a whorl of fibrous tissue. Others have reported moderate to severe adhesions when using MARLEX®.
GORE-TEX® is currently believed to be the most chemically inert polymer and has been found to cause minimal foreign body reaction when implanted. A major problem exists with the use of polytetrafluoroethylene in a contaminated wound as it does not allow for any macromolecular drainage, which limits treatment of infections.
Collagen first gained utility as a material for medical use because it was a natural biological prosthetic substitute that was in abundant supply from various animal sources. The design objectives for the original collagen prosthetics were the same as for synthetic polymer prostheses; the prosthesis should persist and essentially act as an inert material. With these objectives in mind, purification and crosslinking methods were developed to enhance mechanical strength and decrease the degradation rate of the collagen (Chvapil, M., et al (1977) J. Biomed. Mater. Res 11:297-314; Kligman, A. M., et al (1986) J. Dermatol. Surg. Oncol. 12 (4):351-357; Roe, S. C., et al. (1990). Artif. Organ. 14:443-448. Woodroff, E. A. (1978), J. Bioeng. 2:1-10). Crosslinking agents originally used include glutaraldehyde, formaldehyde, polyepoxides, diisocyanates (Borick P. M., et al. (1964) J. Pharm. Sci. 52;1273-1275), and acyl azides. Processed dermal sheep collagen has been studied as an implant for a variety of applications. Before implantation, the sheep dermal collagen is typically tanned with hexamethylenediisocyanate (van Wachem, P. B., et al. Biomaterials 12(March):215-223, 1991) or glutaraldehyde (Rudolphy, V. J., et al. Ann Thorac Surg 52:821-825, 1991). Glutaraldehyde, probably the most widely used and studied crosslinking agent, was also used as a sterilizing agent. In general, these crosslinking agents generated collagenous material which resembled a synthetic material more than a natural biological tissue, both mechanically and biologically.
Crosslinking native collagen reduces the antigenicity of the material (Chvapil, M. (1980) Reconstituted collagen pp. 313-324. In: Viidik, A., Vuust, J. (eds), Biology of Collagen. Academic Press, London; Harjula, A., et al. (1980) Ann. Chir. Gynaecol. 69: 256-262.) by linking the antigenic epitopes rendering them either inaccessible to phagocytosis or unrecognizable by the immune system. There are many known methods of crosslinking collagenous materials. U.S. Pat. No. 5,571,216 details several methods of achieving crosslinking through the heating and joining of free ends of collagen tendrils. U.S. Pat. No. 5,263,983 to Yoshizato details crosslinking by treating collagenous composites with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride. Glutaraldehyde is also employed as a reagent in crosslinking (See U.S. Pat. No. 4,787,900 to Yannas; U.S. Pat. No. 4,597,762 to Walter). However, data from studies using glutaraldehyde as the crosslinking agent are hard to interpret since glutaraldehyde treatment is also known to leave behind cytotoxic residue (Chvapil, M. (1980), supra; Cooke, A., et al. (1983) Br. J. Exp. Path. 64:172-176; Speer, D. P., et al. (1980) J. Biomed. Mater. Res. 14:753-764; Wiebe, D., et al. (1988) Surgery. 104:26-33). It is therefore, possible that the reduced antigenicity associated with glutaraldehyde crosslinking is due to non-specific cytotoxicity rather than a specific effect on antigenic determinants. Glutaraldehyde treatment is an acceptable way to increase durability and reduce antigenicity of collagenous materials as compared to those that are non-crosslinked. However, glutaraldehyde crosslinking collagen materials significantly limits the body's ability to remodel the prosthesis (Roe, S. C., et al. (1990), supra).
All of the above problems associated with traditional materials stem, in part, from the inability of the body to recognize any implant as “inert”. Although biologic in origin, extensive chemical modification of collagen tends to render it as “foreign”. To improve the long term performance of implanted collagenous devices, it is important to retain many of the properties of the natural collagenous tissue. In this “tissue engineering” approach, the prosthesis is designed not as a permanent implant but as a scaffold or template for regeneration or remodeling. Tissue engineering design principles incorporate a requirement for isomorphous tissue replacement, wherein the biodegradation of the implant matrix occurs at about the same functional rate of tissue replacement (Yannas, I. V. (1995) Regeneration Templates. pp. 1619-1635. In: Bronzino, J. D. (ed.), The Biomedical Engineering Handbook, CRC Press, Inc., Boca Raton, Fla.).
When such a prosthesis is implanted, it should immediately serve its requisite mechanical and/or biological function as a body part. The prosthesis should also support appropriate host cellularization by ingrowth of mesenchymal cells, and in time, through isomorphous tissue replacement, be replaced with host tissue, wherein the host tissue is a functional analog of the original tissue. In order to do this, the implant must not elicit a significant humoral immune response or be either cytotoxic or pyrogenic to promote healing and development of the neo-tissue.
Prostheses or prosthetic material derived from isolated collagen molecules, either in powder form or in a solution, have been investigated for surgical repair or for tissue and organ replacement. The source of collagen used in these prosthetic devices is determinate of the prostheses' form and function. U.S. Pat. No. 4,787,900 to Yannas details a process for the creation of prosthetic blood vessels out of a collagenous composite formed, ex vivo, form individual collagen molecules in either powder or solution form. The collagenous compound is a conglomerate of individual collagen molecules and does not retain any of the structural characteristics of the tissue from which the collagen was originally derived. Instead, this collagenous composite is a “tangled mass of collagen fibrils” that is later chemically tailored into the desired shape and thickness required for repairing the specific blood vessel.
Prostheses or prosthetic material derived from explanted mammalian tissue have been widely investigated for surgical repair or for tissue and organ replacement. The tissue is typically processed to remove cellular components leaving a natural tissue matrix. Further processing, such as crosslinking, disinfecting or forming into shapes have also been investigated. U.S. Pat. No. 3,562,820 to Braun discloses tubular, sheet and strip forms of prostheses formed from submucosa adhered together by use of a binder paste such as a collagen fiber paste or by use of an acid or alkaline medium. U.S. Pat. No. 4,502,159 to Woodroof provides a tubular prosthesis formed from pericardial tissue in which the tissue is cleaned of fat, fibers and extraneous debris and then placed in phosphate buffered saline. The pericardial tissue is then placed on a mandrel and the seam is then closed by suture and the tissue is then crosslinked. U.S. Pat. No. 4,703,108 to Silver provides a biodegradable matrix from soluble collagen solutions or insoluble collagen dispersions which are freeze dried and then crosslinked to form a porous collagen matrix. U.S. Pat. No. 4,776,853 to Klement provides a process for preparing biological material for implant that includes extracting cells using a hypertonic solution at an alkaline pH followed by a high salt solution containing detergent; subjecting the tissue to protease free enzyme solution and then an anionic detergent solution. U.S. Pat. No. 4,801,299 to Brendel discloses a method of processing body derived whole structures for implantation by treating the body derived tissue with detergents to remove cellular structures, nucleic acids, and lipids, to leave an extracellular matrix which is then sterilized before implantation. U.S. Pat. No. 4,902,508 to Badylak discloses a three layer tissue graft composition derived from small intestine comprising tunica submucosa, the muscularis mucosa, and stratum compactum of the tunica mucosa. The method of obtaining tissue graft composition comprises abrading, the intestinal tissue followed by treatment with an antibiotic solution. U.S. Pat. No. 5,336,616 to Livesey discloses a method of processing biological tissues by treatment of tissue to remove cells, treatment with a cryoprotectant solution, freezing, rehydration, and finally, innoculation with cells to repopulate the tissue. U.S. Pat. No. 4,597,762 to Walter discloses a method of preparing collagenous prostheses through proteolysis, crosslinking with glutaraldehyde, welding and subsequent sterilization of animal hide or other mammalian tissues.
It is a continuing goal of researchers to develop implantable prostheses which can successfully be used to replace or to facilitate the repair of mammalian tissues, such as abdominal wall defects and vasculature, so that the intrinsic strength, resillience, and biocompatability of the host's own cells may be optimally exploited in the repair process.